Imidazole derivatives having affinity for alpha2 receptors

Details Imidazole derivatives having affinity for alpha2 receptors Imidazole derivatives having affinity for alpha2 receptors

1999-02-02

2001-11-06

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S399000, C514S400000, C548S345100

Reexamination Certificate

active

06313311

ABSTRACT:

The present invention relates to substituted 4(5)-(1-indanyl and 1-indanylmethyl and 1-indanylmethylen)imidazoles and 4(5)-[1-(1,2,3,4-tetrahydronaphthyl and 1,2,3,4-tetrahydronaphthylmethyl and 1,2,3,4-tetrahydronaphthylmethylen]imidazoles and to their isomers, pharmaceutically acceptable salts and esters. It also relates to their preparation, use and to pharmaceutical compositions containing them.
The compounds of the invention have affinity for alpha2 receptors most of them being very selective alpha2 agonists. Accordingly, they are useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances (such as tobacco and narcotics) and different neurological, musculoskeletal, psychiatric and cognition disorders as well as sedative and analgesic agents, nasal decongestants, and adjuncts to anaesthesia.
Gregory G. B., et al describe in J. Org. Chem. (1990), 55, 1479-1483 a new synthesis step for 1-phenylalkyl-1-(4-imidazolyl)-1,2,3,4-tetrahydronaphthalene derivatives which are useful as nonpeptide antagonists of the angiotensin II receptor.
The imidazole derivatives of the invention are either compounds of formula I
n is 0 or 1
R
1
is hydrogen or C
1
-C
4
-alkyl
R
2
is hydrogen or R
2
and R
3
together form a double bond
R
3
is hydrogen or C
1
-C
4
-alkyl or R
2
and R
3
together form a double bond
R
4
is hydrogen, C
1
-C
4
-alkyl, hydroxy or C
1
-C
4
-alkoxy
R
5
is hydrogen or C
1
-C
4
-alkyl or R
4
and R
5
together with the carbon atom to which they are attached form a carbonyl group
R
6
, R
7
and R
8
are each the same or different and are independently hydrogen, C
1
-C
4
-alkyl or C
2
-C
4
-alkenyl, C
3
-C
7
-cycloalkyl, hydroxy, C
1
-C
4
-alkoxy, C
1
-C
4
-hydroxyalkyl, thiol, C
1-4
-alkylthio, C
1-4
-alkylthiol, halogen, trilluoromethyl, nitro or optionally substituted amino
X is —CHR
10
—(CHR
1 1
)
m
—
m is 0 or 1
and R
9
and R
10
are each the same or different and are independently hydrogen or C
1
-C
4
-alkyl;
or a pharmaceutically acceptable ester or salt thereof.
The terms as employed herein have the following meanings: A halogen is e.g. chlorine, bromine or fluorine, preferably it is chlorine or fluorine. The C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy and C
2
-C
4
-alkenyl etc. groups may be branched or straight chain groups. C
3
-C
7
-Cycloalkyl is a saturated cyclic hydrocarbon group having preferably 3 to 5 carbon atoms. Optionally substituted amino is an amino group which is unsubstituted or substituted with a C
1
-C
4
-alkyl group.
When m=n=0
R
3
is preferably hydrogen,
R
4
is preferably hydrogen, hydroxy or C
1
-C
4
-alkoxy, such as ethoxy,
R
5
is preferably hydrogen, or R
4
and R
5
form, together with the carbon atom to which they are attached, a carbonyl group.
R
6
is preferably hydrogen, C
1
-C
4
-alkyl, such as methyl, ethyl, t-butyl, hydroxy or C
1
-C
4
-alkoxy, such as methoxy. For example, R
6
may be C
1
-C
4
-alkyl at position 4, 5 or 6, such as 4-methyl, 4-t-butyl, 5-methyl, 6-methyl, 6-ethyl, 6-t-butyl, 6-i-butyl, hydroxy at position 5 or position 7, or a C
1
-C
4
-alkoxy at position 5, 6 or 7, such as 5-, 6- or 7-methoxy.
More preferably R
6
is hydrogen, 4-methyl, 6-methyl or 7-methoxy.
R
7
is preferably hydrogen, C
1
-C
4
-alkyl, such as, for example methyl or t-butyl, hydroxy or C
1
-C
4
-alkoxy, for example methoxy. For example R
7
may be a C
1
-C
4
-alkyl at position 5, 6 or 7, such as 5-methyl, 7-methyl, 6-t-butyl, 7-hydroxy or 7-methoxy.
More preferably R
7
is hydrogen.
R
8
is preferably hydrogen, hydroxy or C
1
-C
4
-alkoxy, such as methoxy. For example, R
8
may be 6-hydroxy or 7-hydroxy, a C
1
-C
4
-alkoxy at position 6, such as 6-methoxy.
R
9
is preferably hydrogen or methyl.
When n=1 and m=0
R
1
is preferably hydrogen, methyl or ethyl.
R
2
, R
3
and R
9
are preferably hydrogen.
R
4
and R
5
are preferably hydrogen or methyl.
R
6
is preferably hydrogen, C
1
-C
4
-alkyl, such as methyl or t-butyl, hydroxy, C
1
-C
4
-alkoxy, such as methoxy or C
1
-C
4
-hydroxyalkyl, such as hydroxymethyl or halogen. For example, R
6
may be a C
1
-C
4
-alkyl at position 4 or 5, such as 4- or 5-methyl or 4- or 5-t-butyl, 4-, 5-, 6- or 7-hydroxy, a C
1
-C
4
-alkoxy at position 5, 6 or 7 such as 5-, 6- or 7-methoxy or C
1
-C
4
-hydroxyalkyl at position 5 such as 5-hydroxymethyl. R
6
may be halogen at position 5 or 6, such as 5- or 6-fluoro or 5- or 6-bromo.
More preferably R
6
is 4-, 5- or 6-hydroxy.
R
7
is preferably hydrogen, C
1
-C
4
-alkyl, hydroxy, C
1
-C
4
-alkoxy, C
1
-C
4
-hydroxyalkyl or halogen. For example, R
7
may be C
1
-C
4
-alkyl at position 5, 6 or 7, such as 5- or 7-methyl or 5- or 6-t-butyl, 5- or 6-hydroxy, or C
1
-C
4
-alkoxy at position 6, such as 6-methoxy, C
1
-C
4
-hydroxyalkyl at position 6, such as 6-hydroxymethyl or halogen at position 5, such as 5-bromo.
More preferably R
7
is hydrogen, 6-t-butyl, 6-hydroxy or 6-hydroxymethyl.
R
8
is preferably hydrogen, C
1
-C
4
-alkyl, hydroxy, C
1
-C
4
-alkoxy or halogen, for example C
1
-C
4
-alkyl at position 7, such as 7-methyl or 7-t-butyl, 6- or 7-hydroxy or C
1
-C
4
-alkoxy at position 6, such as 6-methoxy or halogen at position 7 such as 7-bromo.
Especially preferably R
6
is hydroxy at the position 4 or 6 of the indane ring and R
7
and R
8
are hydrogen or R
6
is hydroxy at the position 5 of the indane ring and R
7
is hydroxy or C
1
-C
4
-alkyl or C
1
-C
4
-hydroxyalkyl at the position 6 of the indane ring, such as 6-t-butyl or 6-hydroxymethyl and R
8
is hydrogen.
When n=m=1
R
1
, R
2
, R
3
, R
5
, R
9
and R
10
are preferably hydrogen.
R
4
is preferably hydrogen or C
1
-C
4
-alkyl, such as, for example, methyl.
R
6
is preferably at position 5, 6 or 7.
R
6
is preferably hydrogen, hydroxy, C
1
-C
4
-alkoxy, for example methoxy, or halogen. For example, R
6
may be 5-, 6- or 7-methoxy, 6- or 7-hydroxy or halogen at position 6, such as 6-bromo.
R
7
is preferably at position 7.
R
7
is preferably hydrogen or C
1
-C
4
-alkyl, such as, for example, 7-t-butyl or 7-hydroxy.
R
8
is preferably at position 8.
R
8
is preferably hydrogen or halogen such as 8-bromo.
When n=0 and m=1
R
3
, R
4
, R
5
, R
7
, R
8
, R
9
and R
10
are preferably hydrogen.
R
6
is preferably hydrogen or halogen, for example chlorine. R
6
may be a halogen at position 5, such as, for example 5-chloro.
The invention includes within its scope all the possible isomers and stereoisomers, in particular Z and E (cis and trans isomers) and enantiomers.
The compounds of the formula (I) form acid addition salts with both organic and inorganic acids. Typical acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates. Furthermore, compounds wherein one or more of R
4
to R
8
is a hydroxy group form esters and salts with alkali metals and alkaline earth metals. Typical esters include the lower alkyl esters, such as the methyl, ethyl and propyl esters.
The compounds of the invention may be prepared using the following methods. (It is to be noted that in the formulae below, when the imidazole group is protected, the protecting group R′ (benzyl or tntyl) may be attached to either of the two nitrogen atoms of the imidazole ring. Accordingly, the use of 1-benzyl-5-imidazolecarbaldehyde as starting material leads to 1.5 substituted derivatives whereas when trityl is used the substitution is mainly 1.4.)
Synthesis of 4(5)-(1-indanyl)imidazoles and the corresponding 4(5-[1-(1,2,3,4-tetrahydronaohthyl)]imidazoles
Method a
Compounds of formula I wherein n=0 and m=0 or 1 may be prepared by an acid catalyzed cyclization of protected or unprotected 4(5)-(1-hydroxy-3-phenylpropyl or 1-hydroxy-4-phenylbutyl)imidazoles of formulae II and II′, respectively.
Accordingly, the 4(5)-(1-indanyl)imidazoles may be prepared by cyclization of the compound of formula II
wherein R
3
to R
9
are as defined above and R′ is a protecting group, in the presence of an acid

Affiliated with

Also associated with

Rating

Imidazole derivatives having affinity for alpha2 receptors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Imidazole derivatives having affinity for alpha2 receptors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Imidazole derivatives having affinity for alpha2 receptors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2595610